Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs) and for thyroid-stimulating hormone (TSH-R) as model 7TMRs to study their structure and function. During this year, we studied several new aspects of the structure and function of TSH-Rs. 1) An important relatively new observation for TSH-Rs is that they are expressed on cells other than the thyrocyte but the role(s) of TSH-R in these cells is not well understood. One prominent cell that expresses TSH-Rs is the pre-osteoblast that is the precursor for forming new bone. Also, it has been known for a number of years that TSH-R can activate several different signal transduction pathways in model cell systems such as HEK and CHO cells. However, whether these pathways are important in TSH-R signaling that leads to differentiation of cells other than the thyrocyte was not known. We have extended our previous observations of the effect of differentiation of human pre-osteoblasts. We found that different signaling pathways regulate three different bone-specific genes. This important because it is now apparent that drugs to increase bone homeostasis would likely need to activate these several pathways. 2) Graves' ophthalmopathy (GO) is a troublesome component of Graves' disease (GD) that occurs in 25% of GD patients but for which there is no medical therapy. We study GO in cells in primary culture taken from the retro-orbital space of patients with GO at decompression surgery. We use these cells to study GO as there is no animal model of GO. We found a critical interaction between the TSH-R and the receptor for insulin-like growth factor type 1 (IGF-1R) in these cells. We showed that this interaction (cross talk) allowed for a synergistic increase in the production of hyaluronan (hyaluronic acid, HA), which is a major component of the dysregulated extracellular matrix in GO. We have extended these observations. It was proposed by others that there may be immunoglobulins (auto-antibodies; GO-Igs) in the blood of GO patients that can bind to and activate TSH-Rs and IGF-1Rs. We have now shown that no specimen from 42 GO-Ig samples that stimulated HA secretion activates IGF-1R. Yet there are some antibodies generated in the laboratory that inhibit activation of IGF-1R that may have a role in humans to treat GO. This occurs because these ant-IGF-1R antibodies inhibit TSHR/IGF-1R cross talk. These observations allow for the definitive conclusion that IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO. We also published a review article addressing the issue of Future prospects for the treatment of Graves Hyperthyroidism and Eye Disease.